Achievements

Pre-clinical development

  • Pre-clinical assessment of the potential of IGF in activation in the treatment of melanoma. Further assessment of this class of drug is planned in several tumour types with clinical testing of the hypothesis, currently being investigated in preclinical work, that IGF signalling influences DNA damage repair. This work will require development of PD assays for IGF signalling and DNA repair in vivo, for which ECMC support will be essential.
  • Pre-clinical development of IMM47 DC therapy in melanoma.
  • We have discovered a strong interaction of HDAC inhibitors with DNA damaging agents, and have made progress towards identifying the mechanism, with HR23B as a potential biomarker. Using widely available, early generation agents (valproic acid, trichostatin A, SAHA), we have identified a novel, and potentially exploitable interaction between HDAC inhibitors and DNA cross-linking drugs.
  • Preclinical development of high-throughput screening tests to identify radiosensitisers, particularly modulators of DNA repair, which may be used in early phase trials with radiotherapy (Labs of WGM & RAS).
  • Preclinical identification of 6-thioguanine as selectively lethal to BRCA2-mutant cancer cells.
  • We showed a mechanism of resistance to bortezomib through PERK activation, which provides the basis for justification of screening for PERK inhibitors, which is now being funded and taken over by Cancer Research UK CRT.
  • We have discovered a major mechanism of resistance to VEGF inhibitors, activation of notch signalling by Dll4 pathway. We have had access to tumour material from patients treated with Bevacizumab and currently we are carrying out immunohistochemical scoring to assess whether Dll4 expression relates to resistance and therefore provides an important selection for new agents targeting this pathway.
  • We have found that, when anti-angiogenic therapy is given, lipid metabolism pathways are switched on, that are important in survival of cancer cells and hypoxia. We have obtained funding from GlaxoSmithKline to investigate this further and we plan to use inhibitors of fatty acid metabolism and anti-angiogenic drugs in preclinical models prior to clinical trials.
  • Completed pre-clinical development of 111In-DTPA-hEGF. We are currently working with the CR-UK Biotherapeutics Development Unit and Drug Development Office to launch a multi-dose phase I trial of this agent (supported through CR-UK New Agents Committee) in Oct 2010. We have developed a system for computational analysis of gH2AX foci, a possible biomarker for response to this agent.
 

Clinical trials and biomarkers

  • Ongoing phase 2 clinical trial in melanoma patients primed with ISCOMATRIX NY-ESO-1 and boosted with Fowlpox NY-ESO-1.
  • A phase 1 single-agent trial of the Eli-Lilly anti-survivin ASO (LY2181308) has been conducted in non-small cell lung cancer. We are currently preparing for a phase 2 trial of this agent.
  • Phase I trials of CB1954 and EP-0152R (RMH ECMC), GSAO (with Manchester ECMC), OXI-4503 (with Manchester ECMC and Mt Vernon) and Survivin ASO and ATN-224 have been completed, as well as industry sponsored trials of PARP, MEK and IGF1-R inhibitors. Studies of decitabine and ECF (with Imperial ECMC) and Oxilaplatin and 5FU in the neoadjuvant treatment of oesophageal are nearing completion.
  • Early phase work in melanoma with repair and signal transduction inhibitors continues (AZD2281, AZD6244, ABT-888), as do translational studies linked to the large scale trials AVAST-M and EORTC18032.
  • Developed novel protocol to facilitate the activation in vivo of antigen specific B cell responses and enhance generation of antibodies specific for weak immunogens.
  • Attraction of two phase 2 studies to the UK NCRI portfolio for melanoma, CTAAC and TRICC grants awarded for oxaliplatin-radiation phase III study (FOXFIRE) – sample collection twinned with Southampton ECMC.
  • Early phase trials opened to recruitment for radiosensitising agent, nelfinavir, in combination with cytotoxic chemotherapy.
  • Early phase trial in development studying the use of 6-thioguanine in patients with BRCA-defective cancers.
  • We have recruited 29 patients so far into a neoadjuvant study of Bevacizumab pre-operative in breast cancer to ascertain mechanisms of response and resistance involving serial gene array analysis and MRI scans to stratify response by molecular marker changes. This shows three clear patterns of response and we are currently investigating resistance mechanisms in view to preclinical assessment and then clinical studies.
  • Further work on microRNA-210 has demonstrated that it is a powerful predictor of adverse outcome in head and neck cancer as well as breast cancer, and can be analysed in samples which have been extracted from formalin fixed paraffin embedded sections. This marker is now being assessed with funding from TRICC and MRC to analyse three randomised trials comparing hypoxia modulating drugs with radiotherapy to see if we can predict patients who get the most benefit (in collaboration with Professor Catharine West, Manchester).
  • Involvement of our Unit in two Phase I trials of novel IGF1R inhibitors, for which we are the only UK centre.
 

Establishment of dedicated Phase 1 Unit within the ECMC

  • Provides a much greater basis of continuity and a central resource for allocating patients to phase 1 trials, speeding up and enhancing accrual. This is particularly important as many of the clinicians are also leaders of scientific groups, and it enhances their capability to contribute patients to phase 1 trials. ECMC funding has allowed us successfully to qualify and assess biomarkers in several trials of our own, notably those of NY-ESO-01 and CB1954/EP-0152R.